tbuckley/cabot-search huggingface dataset:
miR-181b targets semaphorin 3A to mediate TGF-β–induced endothelial-mesenchymal transition related to atrial fibrillation
Authors: Ying-Ju Lai, Feng-Chun Tsai, Gwo-Jyh Chang, Shang-Hung Chang, Chung-Chi Huang, Wei-Jan Chen, Yung-Hsin Yeh
Journal: Journal of Clinical Investigation (2022)

Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β-treated human AEECs, cardiac-specific TGF-β-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.
Epidural electrical stimulation of the cervical dorsal roots restores voluntary upper limb control in paralyzed monkeys
Authors: Beatrice Barra, Sara Conti, Matthew G. Perich, Katie Zhuang, Giuseppe Schiavone, Florian Fallegger, Katia Galan, Nicholas D. James, Quentin Barraud, Maude Delacombaz, Mélanie Kaeser, Eric M. Rouiller, Tomislav Milekovic, Stephanie Lacour, Jocelyne Bloch, Grégoire Courtine, Marco Capogrosso
Journal: Nature Neuroscience (2022)
Neoadjuvant Chemoimmunotherapy for the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm Phase 2 Clinical Trial
Authors: Zhanjie Zhang, Bian Wu, Gang Peng, Guixiang Xiao, Jing Huang, Qian Ding, Chengzhang Yang, Xingao Xiong, Hui Ma, Liangliang Shi, Jinsong Yang, Xiaohua Hong, Jielin Wei, You Qin, Chao Wan, Yi Zhong, Yan Zhou, Xueyan Zhao, Yangming Leng, Tao Zhang, Gang Wu, Min Yao, Xiaomeng Zhang, Kunyu Yang
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Patients and Methods: In this single-center, single-arm, phase 2 trial, patients with resectable stage III–IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety. Results: Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%–57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%–88.9%). The median follow-up duration was 16.1 months (range, 8.3–28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%–99.4%). Grade 3 neoadjuvant therapy–related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%). Conclusions: Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.
Addressing Residential Segregation as a Social Determinant of Health
Authors: Patrick M. Carter, Marc A. Zimmerman
Journal: JAMA Network Open (2022)

Policing practices have garnered increased national attention in recent years following multiple highly publicized encounters that have resulted in the death of unarmed Black citizens. 1As a public health issue, legal interventions (ie, police or law enforcement interactions) have resulted in more than 5500 fatal and 850 000 nonfatal injuries within the past decade (2011-2020). 2In addition to physical and sexual assaults by police that result in fatal and nonfatal injuries, police-involved violence also includes a range of psychologically harmful (eg, coercion or harassment during police encounters) or neglectful (eg, failure to aid) behaviors. 3Such violence disproportionately affects historically marginalized populations, including American Indian or Alaska Native, Black, and Hispanic communities; lesbian, gay, bisexual, transgender, and queer individuals and individuals with other gender and sexual identities; and economically disenfranchised, disabled, houseless, and
BNT162b2 Vaccine Effectiveness against Omicron in Children 5 to 11 Years of Age
Authors: Chandra J. Cohen-Stavi, Ori Magen, Noam Barda, Shlomit Yaron, Alon Peretz, Doron Netzer, Carlo Giaquinto, Ali Judd, Leonard Leibovici, Miguel A. Hernán, Marc Lipsitch, Ben Y. Reis, Ran D. Balicer, Noa Dagan
Journal: New England Journal of Medicine (2022)

Limited evidence is available on the real-world effectiveness of the BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) and specifically against infection with the omicron variant among children 5 to 11 years of age.
Promoting health beyond prison walls
Authors: None The Lancet Public Health
Journal: The Lancet Public Health (2022)

The Global Prison Trends 2022 report, published on May 11, flags the continuing global failure to reduce prison populations. Governments have been frequently resorting to unnecessary overincarceration under the illusion of solving social problems. But this short-sightedness drives prison overcrowding and poses immense challenges for the healthcare and social reintegration of prisoners. Today, the global prison population is at an all-time high, with several prison systems struggling to even meet the basic needs of prisoners.
The Gut Microbiome Composition Is Altered in Long-standing Type 1 Diabetes and Associates With Glycemic Control and Disease-Related Complications
Authors: Julia I.P. van Heck, Ranko Gacesa, Rinke Stienstra, Jingyuan Fu, Alexandra Zhernakova, Hermie J.M. Harmsen, Rinse K. Weersma, Leo A.B. Joosten, Cees J. Tack
Journal: Diabetes Care (2022)

OBJECTIVE People with type 1 diabetes are at risk for developing micro- and macrovascular complications. Little is known about the gut microbiome in long-standing type 1 diabetes. We explored differences in the gut microbiome of participants with type 1 diabetes compared with healthy control subjects and associated the gut microbiome with diabetes-related complications. RESEARCH DESIGN AND METHODS Microbiome data of 238 participants with type 1 diabetes with an average disease duration of 28 ± 15 years were compared with 2,937 age-, sex-, and BMI-matched individuals. Clinical characteristics and fecal samples were collected, and metagenomic shotgun sequencing was performed. Microbial taxonomy was associated with type 1 diabetes–related characteristics and vascular complications. RESULTS No significant difference in the α-diversity of the gut microbiome was found between participants with type 1 diabetes and healthy control subjects. However, 43 bacterial taxa were significantly depleted in type 1 diabetes, while 37 bacterial taxa were significantly enriched. HbA1c and disease duration explained a significant part of the variation in the gut microbiome (R2 &amp;gt; 0.008, false discovery rate [FDR] &amp;lt;0.05), and HbA1c was significantly associated with the abundance of several microbial species. Additionally, both micro- and macrovascular complications explained a significant part of the variation in the gut microbiome (R2 &amp;gt; 0.0075, FDR &amp;lt; 0.05). Nephropathy was strongly associated with several microbial species. Macrovascular complications displayed similar associations with nephropathy. CONCLUSIONS Our data show that the gut microbiome is altered in people with (long-standing) type 1 diabetes and is associated with glycemic control and diabetes-related complications. As a result of the cross-sectional design, the causality of these relationships remains to be determined.
Mechanistic Insights Into the Heterogeneity of Glucose Response Classes in Youths With Obesity: A Latent Class Trajectory Approach
Authors: Domenico Tricò, Sarah McCollum, Stephanie Samuels, Nicola Santoro, Alfonso Galderisi, Leif Groop, Sonia Caprio, Veronika Shabanova
Journal: Diabetes Care (2022)

OBJECTIVE In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS Latent class trajectory analysis was used to identify various glucose response profiles to a nine-point OGTT in 2,378 participants in the Yale Pathogenesis of Youth-Onset T2D study, of whom 1,190 had available TCF7L2 genotyping and 358 had multiple OGTTs over a 5 year follow-up. Insulin sensitivity, clearance, and β-cell function were estimated by glucose, insulin, and C-peptide modeling. RESULTS Four latent classes (1 to 4) were identified based on increasing areas under the curve for glucose. Participants in class 3 and 4 had the worst metabolic and genetic risk profiles, featuring impaired insulin sensitivity, clearance, and β-cell function. Model-predicted probability to be classified as class 1 and 4 increased across ages, while insulin sensitivity and clearance showed transient reductions and β-cell function progressively declined. Insulin sensitivity was the strongest determinant of class assignment at enrollment and of the longitudinal change from class 1 and 2 to higher classes. Transitions between classes 3 and 4 were explained only by changes in β-cell glucose sensitivity. CONCLUSIONS We identified four glucose response classes in youths with obesity with different genetic risk profiles and progressive impairment in insulin kinetics and action. Insulin sensitivity was the main determinant in the transition between lower and higher glucose classes across ages. In contrast, transitions between the two worst glucose classes were driven only by β-cell glucose sensitivity.
Duration of Shedding of Culturable Virus in SARS-CoV-2 Omicron (BA.1) Infection
Authors: Julie Boucau, Caitlin Marino, James Regan, Rockib Uddin, Manish C Choudhary, James P Flynn, Geoffrey Chen, Ashley M Stuckwisch, Josh Mathews, May Y Liew, Arshdeep Singh, Taryn Lipiner, Autumn Kittilson, Meghan Melberg, Yijia Li, Rebecca F Gilbert, Zahra Reynolds, Surabhi L Iyer, Grace C Chamberlin, Tammy D Vyas, Marcia B Goldberg, Jatin M Vyas, Jonathan Z Li, Jacob E Lemieux, Mark J Siedner, Amy K Barczak
Journal: New England Journal of Medicine (2022)

Duration of Shedding of Culturable Virus in SARS-CoV-2 Omicron (BA.1) InfectionTo the Editor: The B.1.1.529(omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a shorter incubation period and a higher transmission rate than previous variants. 1,2Recently, the Centers for Disease Control and Prevention recommended shortening the strict isolation period for infected persons in non-health care settings from 10 days to 5 days after symptom onset or after the initial positive test, followed by 5 days of masking. 3However, the viral decay kinetics of the omicron variant and the duration of shedding of culturable virus have not been well characterized.We used longitudinal sampling of nasal swabs for determination of viral load, sequencing, and viral culture in outpatients with newly diagnosed coronavirus disease 2019 (Covid-19). 4rom July 2021 through January 2022, we enrolled 66 participants, including 32 with samples that were sequenced and identified as the B.1.617.2 (delta) variant and 34 with samples that were sequenced and identified as the omicron subvariant BA.1, inclusive of sublineages.Participants who received Covid-19-specific therapies were excluded; all but 1 participant had symptomatic infection.This study was approved by the institutional review board and the institutional biosafety committee at Mass General Brigham, and informed consent was obtained from all the participants.The characteristics of the participants were similar in the two variant groups except that more participants with omicron infection had received a booster vaccine than had those with delta infection (35% vs. 3%) (Tables S1 andS2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).In an analysis in which a Cox proportional-hazards model that adjusted for age, sex, and vaccination status
Outsourcing health-care services to the private sector and treatable mortality rates in England, 2013–20: an observational study of NHS privatisation
Authors: Benjamin Goodair, Aaron Reeves
Journal: The Lancet Public Health (2022)

BackgroundThe effects of outsourcing health services to for-profit providers are contested, with some arguing that introducing such providers will improve performance through additional competition while others worry that this will lead to cost cutting and poorer outcomes for patients. We aimed to examine this debate by empirically evaluating the impact of outsourced spending to private providers, following the 2012 Health and Social Care Act, on treatable mortality rates and the quality of health-care services in England.MethodsFor this observational study, we used a novel database composed of parsable procurement contracts between April 1, 2013, and Feb 29, 2020 (n=645 674, value >£25 000, total value £204·1 billion), across 173 clinical commissioning groups (CCGs; regional health boards) in England. Data were compiled from 12 709 heterogenous expenditure files primarily scraped from commissioner websites with supplier names matched to registers identifying them as National Health Service (NHS) organisations, for-profit companies, or charities. We supplemented these data with rates of local mortality from causes that should be treatable by medical intervention, indicating the quality of health-care services. We used multivariate longitudinal regression models with fixed effects at the CCG level to analyse the association of for-profit outsourcing on treatable mortality rates in the following year. We used the average marginal effects to estimate total additional deaths attributable to changes in for-profit outsourcing. We provided alternative model specifications to test the robustness of our findings, match on background characteristics, examine the potential impact of measurement error, and adjust for possible confounding factors such as population demographics, total CCG expenditure, and local authority expenditure.FindingsWe found that an annual increase of one percentage point of outsourcing to the private for-profit sector corresponded with an annual increase in treatable mortality of 0·38% (95% CI 0·22–0·55; p=0·0016) or 0·29 (95% CI 0·09–0·49; p=0·0041) deaths per 100 000 population in the following year. This finding was robust to matching on background characteristics, adjusting for possible confounding factors, and measurement error in our dataset. Changes to for-profit outsourcing since 2014 were associated with an additional 557 (95% CI 153–961) treatable deaths across the 173 CCGs.InterpretationThe privatisation of the NHS in England, through the outsourcing of services to for-profit companies, consistently increased in 2013–20. Private sector outsourcing corresponded with significantly increased rates of treatable mortality, potentially as a result of a decline in the quality of health-care services.FundingWellcome Trust.
Impact of prison security level on mortality
Authors: Anna Scheyett
Journal: The Lancet Public Health (2022)

A great deal of research has shown that there is an increased risk of death after release from prison, including for violent deaths and deaths by natural causes.1,2 In their Article, Anne Bukten and colleagues3 engage in a more nuanced examination of this risk, comparing risks of death between individuals released from high-security prisons with those from low-security prisons, and controlling for a range of factors (eg, age, gender, type of crime, and length of prison sentence). The authors' findings indicate that mortality risks for releasees from high-security prisons are higher than for those from low-security prisons and that this is true for both external and internal causes of death.
Melatonin alleviates alcoholic liver disease via EGFR–BRG1–TERT axis regulation
Authors: Zhaodi Che, Yali Song, Chengfang Xu, Wei Li, Zhiyong Dong, Cunchuan Wang, Yixing Ren, Kwok-Fai So, George L. Tipoe, Fei Wang, Jia Xiao
Journal: Acta Pharmaceutica Sinica B (2022)

Chronic alcohol consumption causes liver steatosis, cell death, and inflammation. Melatonin (MLT) is reported to alleviate alcoholic liver disease (ALD)-induced injury. However, its direct regulating targets in hepatocytes are not fully understood. In the current study, a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT. MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models (optimal doses of 10 μmol/L and 5 mg/kg, respectively), including lowered liver steatosis, cell death, and inflammation. RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase (TERT) was a key downstream effector of MLT. Biophysical assay found that epidermal growth factor receptor (EGFR) on the hepatocyte surface was a direct binding and regulating target of MLT. Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection, partly through the regulation of nuclear brahma-related gene-1 (BRG1). Long-term administration (90 days) of MLT in healthy mice did not cause evident adverse effect. In conclusion, MLT is an efficacious and safe agent for ALD alleviation. Its direct regulating target in hepatocytes is EGFR and downstream BRG1-TERT axis. MLT might be used as a complimentary agent for alcoholics.
Virotherapy for Brain Tumors — Defining the Path to Success
Authors: Evanthia Galanis
Journal: New England Journal of Medicine (2022)

Most high-grade gliomas are associated with dismal survival in both adults and children, even after aggressive treatment. Despite initial promise, immunotherapy with immune checkpoint inhibitors or peptide vaccines has failed to show efficacy in phase 3, randomized trials involving patients with glioblastoma,1,2 the most common World Health Organization grade IV glioma in adults. The lack of progress in developing effective immunotherapies for adult and pediatric high-grade glioma can be explained by several factors, including scarcity of tumor infiltrating lymphocytes, T-cell exhaustion, low somatic mutational load with decreased burden of tumor-specific antigens, and systemic immunosuppression, both tumor- and treatment-induced. In the . . .
Observed protection against SARS-CoV-2 reinfection following a primary infection: A Danish cohort study among unvaccinated using two years of nationwide PCR-test data
Authors: Daniela Michlmayr, Christian Holm Hansen, Sophie Madeleine Gubbels, Palle Valentiner-Branth, Peter Bager, Niels Obel, Birgitte Drewes, Camilla Holten Møller, Frederik Trier Møller, Rebecca Legarth, Kåre Mølbak, Steen Ethelberg
Journal: The Lancet Regional Health - Europe (2022)
Convergence and Divergence of Rare Genetic Disorders on Brain Phenotypes
Authors: Armin Raznahan, Hyejung Won, David C. Glahn, Sébastien Jacquemont
Journal: JAMA Psychiatry (2022)

<h3>Importance</h3> Rare genetic disorders modulating gene expression—as exemplified by gene dosage disorders (GDDs)—represent a collectively common set of high-risk factors for neuropsychiatric illness. Research on GDDs is rapidly expanding because these variants have high effect sizes and a known genetic basis. Moreover, the prevalence of recurrent GDDs (encompassing aneuploidies and certain copy number variations) enables genetic-first phenotypic characterization of the same GDD across multiple individuals, thereby offering a unique window into genetic influences on the human brain and behavior. However, the rapid growth of GDD research has unveiled perplexing phenotypic convergences and divergences across genomic loci; while phenotypic profiles may be specifically associated with a genomic variant, individual behavioral and neuroimaging traits appear to be nonspecifically influenced by most GDDs. <h3>Observations</h3> This complexity is addressed by (1) providing an accessible survey of genotype-phenotype mappings across different GDDs, focusing on psychopathology, cognition, and brain anatomy, and (2) detailing both methodological and mechanistic sources for observed phenotypic convergences and divergences. This effort yields methodological recommendations for future comparative phenotypic research on GDDs as well as a set of new testable hypotheses regarding aspects of early brain patterning that might govern the complex mapping of genetic risk onto phenotypic variation in neuropsychiatric disorders. <h3>Conclusions and Relevance</h3> A roadmap is provided to boost accurate measurement and mechanistic interrogation of phenotypic convergence and divergence across multiple GDDs. Pursuing the questions posed by GDDs could substantially improve our taxonomical, neurobiological, and translational understanding of neuropsychiatric illness.